Field of the Disclosure
This disclosure relates to the treatment and prevention of Staphylococcus aureus (S. aureus) infection. In particular, the disclosure provides compositions and methods for preventing S. aureus infection and treating a disease caused by a leukocidin, e.g., Panton-Valentine leukocidin (PVL) or gamma-hemolysin expressing S. aureus infection.
Background of the Disclosure
Staphylococcus aureus (SA) is a gram positive human pathogen that is associated with or causes a wide range of pathologies ranging from skin and soft tissue infections to life-threatening systemic infections, e.g., minor skin infections such as pimples, impetigo, boils (furuncles), cellulitis folliculitis, carbuncles, scalded skin syndrome, and abscesses, to life-threatening deep infections such as pneumonia, sepsis, endocarditis, meningitis, post-operative wound infections, septicemia, and toxic shock syndrome (Nizet, V., J Allergy Clin Immunol, 2007. 120(1): p. 13-22; Kotzin, et al., Adv Immunol, 1993. 54: p. 99-166; Meyer et al., Int J Infect Dis, 2001. 5(3): p. 163-6; Schuberth et al., Vet Microbiol, 2001. 82(2): p. 187-99; and Silverstein et al., in Microbiology, Davis et al., eds. (Lippincott, Philadelphia, 1990), pp. 485-506).
Pneumonia is one of the most severe and prominent complications of S. aureus infection leading with 50,000 cases per year in the U.S. alone (Kuehnert, et al., Emerg. Infect. Dis. 11:868-872, 2005). S. aureus pneumonia has been traditionally ventilator associated but in recent years it has been recognized also as a major cause of community acquired pneumonia primarily in otherwise healthy children and young individuals.
The range of SA-associated pathologies reflects the diverse abilities of this microbe to escape the innate and adaptive immune response using multiple virulence factors including coagulase, capsular polysaccharides, adhesins, proteases, exoproteins that inactivate the complement system, pore-forming toxins, and other innate response mediators (Nizet, V., J Allergy Clin Immunol, 2007. 120(1): p. 13-22; Tristan et al., J Hosp Infect, 2007. 65 Suppl 2: p. 105-9). The rapid spread of methicillin resistant SA (MRSA) underscores the importance of developing vaccines for prevention or reduction of severity of MRSA infections. Most previous approaches for vaccine development have ignored the importance of including attenuated toxin components to disarm the immune evasion strategies of SA.
A significant increase in S. aureus isolates that exhibit resistance to most of the antibiotics currently available to treat infections has been observed in hospitals throughout the world. While MRSA strains were initially limited to health care settings, recent epidemics of community associated S. aureus (CA-MRSA) have been reported that cause severe disease in an otherwise healthy population. To date, five CA-MRSA clonal lineages are associated with these outbreaks: the Midwest clone (USA400, CC1), the European clone (CC80), the Southwest-Pacific Oceania clone (CC30), the Pacific clone (CC59), and the Pandemic clone (USA300, CC8). In addition to SCCmec IV, a characteristic feature of these major CA-MRSA lineages is that they have the lukPV operon encoding the Panton Valentine Leukocidin (PVL) (Diep, B. A. and M. Otto, Trends Microbiol, 2008. 16(8): p. 361-9), carried by the lysogenic phages ϕSLT, ϕPVL, ϕSA2MW and ϕSA2usa (Diep et al., Lancet, 2006. 367(9512): p. 731-9; Kaneko et al., Gene, 1998. 215(1): p. 57-67; Narita et al., Gene, 2001. 268(1-2): p. 195-206). The development of penicillin to combat S. aureus was a major advance in infection control and treatment. Unfortunately, penicillin-resistant organisms quickly emerged and the need for new antibiotics was paramount. With the introduction of every new antibiotic, S. aureus has been able to counter with β-lactamases, altered penicillin-binding proteins, and mutated cell membrane proteins allowing the bacterium to persist. Consequently, methicillin-resistant S. aureus (MRSA) and multidrug resistant organisms have emerged and established major footholds in hospitals and nursing homes around the world. (Chambers, H. F., Clin Microbiol Rev., 1:173, 1988; and Mulligan, M. E., et al., Am J Med., 94:313, 1993). Today, almost half of the Staphylococcal strains causing nosocomial infections are resistant to all antibiotics except vancomycin and linezolid. Since many vancomycin intermediate resistant S. aureus (VISA) among MRSA, and a few vancomycin resistant S. aureus, have been reported in the literature, it appears to be only a matter of time before vancomycin will become ineffective as well. (Appelbaum P C., Clin Microbiol Infect., 12 Suppl 1:16-23, 2006).
Natural immunity to S. aureus infections remains poorly understood. Typically, healthy humans and animals exhibit a high degree of innate resistance to S. aureus infections. Protection is attributed to intact epithelial and mucosal barriers and normal cellular and humoral responses. Titers of antibodies to S. aureus components are elevated after severe infections (Ryding et al., J Med Microbiol, 43(5):328-334, 1995), however to date there is no serological evidence of a correlation between these acquired antibody titers and human immunity.
Pore forming toxins that are secreted by S. aureus are crucial to its immune evasion. These toxins may create a survival advantage for the bacteria by forming pores into the membrane of target cells, inducing cell death and weakening the host during the first stages of infection. Because of the limited treatment modalities for S. aureus infection, the emergence of methicillin-resistant S. aureus poses a tremendous public health threat. While the molecular basis of the disease remains unclear, community-associated MRSA infection is closely linked to the presence of a Panton-Valentine leukocidin (PVL), a bipartite toxin consisting of the ˜34 kDa LukF-PV and the ˜32 kDa LukS-PV proteins (H. F. Chambers. The New England Journal of Medicine 352, 1485-1487, 2005). The function of the two PVL components (LukF-PV and LukS-PV) is synergistic and requires a sequence of events at the membrane surface of the target cell (J. Kaneko and Y. Kamio. Bioscience, Biotechnology, and Biochemistry 68, 981-1003, 2004). In the first step, the secreted, water-soluble LukF-PV and LukS-PV monomers aggregate on the membrane surface, and subsequently assemble into heterodimers. In a stepwise fashion, these heterodimers further oligomerize into heterotetramers that are characterized by alternating LukF-PV and LukS-PV subunits. These heterotetramers further assemble into an octameric, disc-like structure that is comprised of alternating LukS-PV and LukF-PV subunits in a 1:1 stoichiometry (L. Jayasinghe and H. Bayley. Protein Sci 14, 2550-2561, 2005). At this stage, experimental data indicates that PVL exists as an octamer in pre-pore conformation that is not fully functional and not transversing the cell membrane. Subsequently, the pre-pore structure undergoes major conformational changes that result in the formation of a single transmembrane pore that allows the influx of calcium ions, leading to cell death (V. T. Nguyen, Y. Kamio, and H. Higuchi. The EMBO Journal 22, 4968-4979, 2003). PVL causes cytolysis resulting in loss of immune cells such as neutrophils and may also cause tissue damage promoting bacterial dissemination. PVL is believed to be involved in pathogenesis of invasive pneumonia and skin infections.
Accordingly, there remains a need in the art for compositions and methods that can safely confer immunity to PVL-expressing S. aureus. 